Better survival and prognosis in SCLC survivors after combined second primary malignancies: A SEER database-based study

With recent advances in treatment modalities, the survival time for patients with small cell lung cancer (SCLC) has increased, along with the likelihood of recurrence of a second primary tumor. However, patient treatment options and prognosis remain uncertain. This research evaluated the survival rates of patients with SCLC with a second malignancy, aiming to provide new insights and statistics on whether to proceed with more active therapy. SCLC patients were selected based on the Surveillance, Epidemiology, and End Results (SEER) database, updated on April 15, 2021. We defined those with SCLC followed by other cancers (1st of 2 or more primaries) in the sequence number as S-second primary malignant cancer (S-SPM). Those who had other cancers followed by SCLC (2nd of 2 or more primaries) were defined as OC-SCLC. We performed Kaplan–Meier survival analysis, life table analysis, univariate analysis, stratified analysis, and multiple regression analysis of patient data. We considered the difference statistically meaningful at P < .05. After selection, data for 88,448 participants from the SEER database was included in our analysis. The mean survival time for patients with S-SPM was 69.349 months (95% confidence interval [CI]: 65.939, 72.759), and the medium duration of survival was 34 months (95% CI: 29.900, 38.100). Univariate analysis showed that for overall survival, the hazard ratio (HR) of S-SPM was 0.367 (95% CI: 0.351, 0.383), which was 0.633 lower than that of patients with solitary SCLC and 0.606 lower than that of patients with OC-SCLC. For cancer-specific survival (CSS), the HR of S-SPM was 0.285 (95% CI: 0.271, 0.301), which was 0.715 lower than for patients with solitary SCLC and 0.608 lower than that for patients with OC-SCLC. Multiple regression analysis showed that the HR values of S-SPM were lower than those of patients with single SCLC and those with OC-SCLC, before and after adjustment for variables. Kaplan–Meier survival curves showed that patients with S-SPM had significantly better survival times than the other groups. The survival time and prognosis of patients with S-SPM were clearly superior to those with single SCLC and OC-SCLC.


Introduction
Lung cancer remains the world's deadliest disease, accounting for 1 quarter of deaths from all cancers. Histologically, pulmonary cancers are separated into 2 major categories: non-small cell lung cancer and small cell lung cancer (SCLC). SCLC represents an estimated 13% to 15% of lung cancer. [1,2] SCLC is notorious for its high level of aggressiveness. SCLC exhibits a high frequency of variants in both tumor suppressors and oncogenes [3,4] and is highly metastatic, [5][6][7] with nearly 70% of patients already having metastasis to lymph nodes and to distant sites when diagnosed. In 2013, SCLC was nominated as "persistent cancer" by the National Cancer Institute. [8] These observations underscore the poor prognosis of SCLC. Treatment of SCLC has been less than satisfactory. With advances in the treatment modalities of SCLC in recent years, the survival time of patients with SCLC has been extended, while the probability these patients developing a second primary tumor during their survival has increased. [9] This poses new challenges for clinicians.
Second primary malignant cancer (SPM) refers to the occurrence in a single or multiple organs of the same individual, developing after the first primary malignancy, independent of the first primary malignancy, rather than metastasis or recurrence. [10][11][12] SPMs appear essentially as a result of acquired genetic mutations or inheritance and might occur very late or within a short period of time following therapy for the first primary tumor, possibly indicating potential genetic or immune deficiency of the patient, genetic damage related to therapy, or environmental contact with carcinogens. [13][14][15] As the number of patients with SCLC with comorbid second primary tumors continues to increase, there is growing concern about this phenomenon. However, few studies have reported patients with SCLC with a concurrent second primary tumor during survival, which negatively affects the development of treatment plans for patients with second cancers. Therefore, further study of this phenomenon is necessary. The present study analyzed the latest SCLC statistics contained in the Surveillance, Epidemiology, and End Results (SEER) database for 88,448 patients with SCLC. SEER is the definitive U.S. cancer statistics database, which captures information on the incidence, fatality rates, and disease status among millions of patients with malignancies in certain U.S. states and counties. The goals of this research were to compare the clinical results of patients with SCLC complicated by a second primary tumor during survival with those of patients with SCLC alone and patients with other cancers with concurrent SCLC during their survival, and to assess and forecast the survival of patients with SCLC connected with a second primary tumor, providing new data and insights about whether to provide aggressive therapy.

Data source
Using the updated SEER data from April

Data processing
We removed 707 missing values from the different variables and then removed 2177 items from the following 5 variables with less data (3rd of 3 or more primaries; 4th of 4 or more primaries; 5th of 5 or more primaries; 6th of 6 or more primaries; 7th of 7 or more primaries). A total of 88,448 individuals with SCLC were ultimately enrolled in our study (Fig. 1). Individual entries were integrated and grouped, and for a more concise description of our study, we defined those with SCLC Figure 1. Data screening chart for patients with SCLC. SCLC = small cell lung cancer. www.md-journal.com followed by other cancers (1st of 2 or more primaries) in the sequence number as S-SPM. Those who had other cancers (OC) followed by SCLC (2nd of 2 or more primaries) were defined as OC-SCLC.

Statistical analysis
The statistical analysis was performed using statistics as a function of frequency and using SPSS v.24 (IBM Corp., Armonk, NY). Trends in survival time were plotted for different subgroups using GraphPad Prism 8 (GraphPad Inc., La Jolla, CA). Data were analyzed using the statistical package R version 3.6.3 [16] (R Foundation for Statistical Computing. URL https:// www.R-project.org/) and Empower Stats [17] (https://www. empowerstats.net/cn/, X&Y solutions Inc. Boston, MA). To investigate the differences in patient prognosis, we carried out univariate analysis, Kaplan-Meier survival analysis, life table analysis, and stratified analysis of patient data. We considered significant differences statistically at P < .05. Furthermore, we performed a multiple regression analysis, in which the sequence number was used as the exposure variable, and status and cause of death recoded were used as the outcome variables. Nonadjusted meant without any adjustment. The adjust I model was adjusted by age, race, and sex. The adjust II model was adjusted by age, chemotherapy, cancer-directed surgery, diagnostic confirmation, grade, laterality, marital status, origin, PRCDA, race, radiation, regional nodes positive, sex, and summary stage.

Ethics declaration
The Ethical Review Committee of the National Center for Health Statistics approved all SEER protocols and obtained written informed consent from all participants.

Result
After screening, a total of 88,448 participants in the SEER database were included in our analysis, of whom 55.046% were male, 10.053% were over 80 years of age, 97.251% were Non-Spanish-Hispanic-Latino, 38.195% had undifferentiated SCLC, and 32.760% had distant metastases. Among the patients, 45.740% had a history of radiation therapy, 70.562% had a history of chemotherapy, 2.967% had a history of surgery, 55.586% had a companion, and 86.958% of deaths were directly attributable to SCLC. Baseline data for the rest of the population are detailed in Table 1.
Univariate analysis of SCLC revealed that patients with S-SPM had significantly longer survival times than patients with SCLC only and those with OC-SCLCs. In terms of overall survival (OS), the hazard ratio (HR) for patients with S-SPM was 0.367 (95% confidence interval [CI]: 0.351, 0.383), a decrease of 0.633 compared with patients with SCLC alone. In terms of cancer-specific survival (CSS), the HR for patients with S-SPM was 0.285 (95% CI: 0.271, 0.301), a decrease of 0.715 compared with patients with SCLC alone. Both P values were less than 0.05. In patients with OC-SCLC, the HR was 0.973 (95% CI: 0.954, 0.993) for OS, an increase of 0.606 compared with that of patients with S-SPM, and 0.893 (95% CI: 0.874, 0.912) for CSS, an increase of 0.608 compared with that of patients with S-SPM, both had P values less than 0.05. The main covariates in this study were sex, age, race, origin, PRCDA, grade, laterality, diagnostic confirmation, summary stage, radiation, chemotherapy, cancer-directed surgery, regional nodes positive, and marital status. The HR values, 95% CIs and P values for the above covariates are detailed in Table 2. We also performed a stratified analysis, which confirmed that patients with S-SPM had a clearly longer survival duration than patients with SCLC only and those with OC-SCLC (see Table S1, http://links.lww. com/MD/I380, Supplemental Content, which illustrates the stratified analysis of SCLC).
Multiple regression analysis demonstrated that patients with S-SPM had significantly better survival times than the other groups. In terms of OS, before adjustment for variables, the HR for patients with S-SPM was 0.367 (95% CI: 0.351, 0.383), which was 0.633 lower than that for patients with SCLC only and 0.606 lower than that for patients with OC-SCLC. In terms of CSS, the HR before adjustment for variables was 0.285 (95% CI: 0.271, 0.301) in patients with S-SPM, which was 0.715 lower than that in patients with SCLC only and 0.608 lower than in patients with OC-SCLC. With survival months as a time variable, sequence number as an exposure variable, and status and cause of death recoding as outcome variables, the results remained consistent with the non-adjusted results (Table 3).
To further analyze the survival characteristics of patients with S-SPM, we produced Kaplan-Meier survival curves, including OS and CSS, which demonstrated that patients with S-SPM had clearly better survival than those with single-onset SCLC or OC-SCLC (Fig. 2). We also performed Kaplan-Meier survival analysis of each covariate, and covariate survival curves are shown in Figure 3.
The  15.171), and the median duration of survival was 7 months (95% CI: 6.790, 7.210). The survival time of patients with S-SPM was significantly better than that of patients with SCLC only or OC-SCLC in terms of mean survival time and median survival time ( Table 4). The survival rate for all SCLC patients was 44% at 6 months, 24% at 1 year, 15% at 18 months, 7% at 3 years, 5% at 5 years, and 2% at 10 years. The survival rate of patients with S-SPM was 78% at 6 months, 67% at 1 year, 60% at 18 months, 48% at 3 years, 39% at 5 years, and 21% at 10 years. In terms of survival at all time periods, patients with S-SPM had significantly longer survival times than the other groups (Table 5).

Discussion
Currently, the number of patients with 2 or more malignancies is increasing. We believe that there may be several reasons for this phenomenon. The increased life expectancy of people because of better treatment for cardiovascular diseases has certainly led to a general increase in the prevalence of malignant tumors. In addition, the increased utilization of chemotherapy and radiotherapy for the first tumor might have increased the probability of genetic mutations and thus the number of secondary cancers. [18,19] Previous studies have shown that as survival time increases, cancer survivors experience a higher than average risk of developing other cancers secondary to the original cancer. [20][21][22] However, multiple primary cancer treatment options are different from those for recurrent and metastatic cancers, and often require a combination of multiple therapies, which is a challenge for health care professionals. Previous studies have addressed the incidence and survival of multiple primary cancers [23][24][25] ; however, these studies had a low volume of case data and a relatively homogeneous approach. The follow-up data for small cell carcinoma in SEER was updated in April 2021; therefore, a more in-depth study of SCLC based on the most recent data is required. Medicine Table 1 Baseline characteristics of participants (N = 88448).  Among patients with malignancy, the development of new cancers in cancer survivors is often regarded as a poor prognostic risk factor. Priante et al [26] retrospectively studied 624 patients who had upper respiratory tract squamous cell carcinoma and analyzed their likelihood for progression to a second primary tumor and their survival rates. The results showed that the 5-year survival rate for this cancer secondary to a second primary tumor was only 32.2%. Patrucco et al [27] demonstrated that more than half of patients with head and neck cancer (51.9%) died because of a second primary tumor, and that a second tumor significantly worsened patient prognosis and further reduced OS. However, the above conclusions might not apply to individuals with lung cancer. Duchateau et al [28] demonstrated that patients with a second tumor in non-small cell lung cancer tended to experience better OS than patients without a second primary tumor. This is similar to our findings; however, that study was not conducted on patients with SCLC. There are fewer studies on patients with SCLC secondary to multiple cancers, and there is increasing concern about the therapy and prognosis for patients with S-SPM; therefore, there is a need for a more in-depth study on SCLC.
After analysis, we found that patients with S-SPM had significantly longer median survival and long-term survival than patients with SCLC only or OC-SCLC. There might be several explanations for this phenomenon. First, patients with SCLC who had developed a second cancer were generally in better health and more psychologically active, while patients with SCLC only might die prematurely because of poorer health or higher tumor malignancy; therefore, patients with S-SPM might experience longer survival than those with SCLC alone. Second, when cancer survivors of SCLC develop a second cancer, inevitably additional anti-tumor treatments are administered against the second cancer, and these subsequent treatments might simultaneously act as anti-SCLC therapies. Thirdly, patients with SCLC generally show a poor response to immune checkpoint blockade, [29] and patients with SCLC alone might have a deficiency in immune surveillance, resulting in "immune escape" without activation of the immune system against SCLC. However, the second cancer in patients with S-SPM might activate not only the body's immune mechanisms against the secondary cancer, but also the immune mechanisms associated with SCLC and act as an anti-SCLC agent.
The study by Heyne et al [30] concluded that patients with SCLC who had a second primary tumor had an even higher mortality rate than patients with recurrent SCLC, which is contrary to our findings. Heyne et al only analyzed 14 eligible patients and the Table 3 Multiple regression analysis of small cell lung cancer.

Exposure
Non-adjusted P value Adjust I P value Adjust II P value Status Sequence number One primary only Reference [1] Reference [1] Reference [1]  One primary only Reference [1] Reference [1] Reference [  amount of data was so small that bias in the data analysis was inevitable. A study by Aguiló et al [31] analyzed all 2030 patients diagnosed with lung cancer, including SCLC, at a local hospital between 1990 and 2004, and concluded that multiple primary cancers did not lead to a poorer prognosis. However, the data in that study were not up to date and the amount of data was small. Outdated data do not adequately represent the SCLC population, so their conclusions are controversial. In contrast, our research involved an large sample size, including 88,448 eligible patients, and we performed univariate analysis, Kaplan-Meier survival analysis, life table analysis, and multiple regression analysis with multivariate adjustment to eliminate the interference of other covariates. Thus, our study is more convincing.
Our research has some limitations. First, this was a retrospective analysis, and further clinical and basic studies are needed to confirm our results. Second, although 27.8% of the U.S. population is already covered by the SEER database, our research would have been more convincing if we had access to more data, such as the entire world's SCLC data.

Conclusions
By analyzing 88,448 patients with SCLC in the SEER database, we found that the duration of survival was clearly superior for patients with S-SPM than for patients with SCLC only or OC-SCLC. We also noted that the occurrence of SPM in patients with SCLC did not necessarily lead to a poor prognosis. When patients with SCLC develop a second cancer during survival, they should receive more aggressive treatment and should not give up treatment easily. The findings of the present study might provide valuable insights into the ongoing monitoring of cancer survivors with combined SPM in SCLC.